Diels alder adducts of bis(trifluoromethyl)thioketene

ABSTRACT

DIELS-ALDER REACTION OF BIS(TRIFLUOROMETHYL)THIOKETENE WITH CONJUGATED CYCLIC DIENES RESULTS IN HEXAFLUOROISOPROPYLIDENEDIHYDROTHIOPYRANS. THESE COMPOUNDS, AND CERTAIN DERIVATIVE THEREOF, HAVE ANTI-INFLAMMATORY PROPERTIES.

United States Patent 3,752,827 DIELS-ALDER ADDUCTS 0F BIS(TRIFLUOR0- METHYLYIHIOKETENE Maynard Stanley Raasch, Wilmington, Del., assignor to du Pont de Nemours and Company, Wilmington,

No Drawing. Continuation-impart of abandoned application Ser. No. 31,392, Apr. 23, 1970. This application Mar. 16, 1971, Ser. No. 124,989

Int. Cl. C07d 65/04 US. Cl. 260-327 TH 10 Claims ABSTRACT OF THE DISCLOSURE Diels-Alder reaction of bis(trifluoromethyl)thioketene with conjugated cyclic dienes results in hexafiuoroisopropylidenedihydrothiopyrans. These compounds, and certain derivatives thereof, have anti-inflammatory properties.

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of my copending application Ser. No. 31,392, filed April 23, 1970, abandoned.

BACKGROUND OF THE INVENTION Field of the invention DESCRIPTION OF THE INVENTION 3 p ,e (C,F,3)

wherein n is 0, 1 or 2;

Y and Z each represent H or together represent a carboncarbon bond;

R and R alike or difierent, are H, alkyl or alkoxy of up to 4 carobn atoms, or cycloalkyl of up to 6 carbon atoms;

3,752,827 Patented Aug. 14, 1973 R and R alike or different, are H, alkyl of up to 4 carbon atoms, cycloalkyl of up to 6 carbon atoms, or halogen, i.e. F, Cl, Br or I;

X is a bridging means consisting of divalent radicals of R and R alike or different, are H, alkyl or alkenyl of up to 4 carbons, cycloalkyl of 5-6 carbons, alkoxy of up to 6 carbons, Cl, or Br, with the proviso that only one of R and R is Cl or Br; and when joined together, alkylene of 2-6 chain carbon atoms, e.g. ethylene and hexamethylene, or a trimethylenedioxy; and

Y and Z each represent H or together represent a carbon-carbon bond.

The total carbons of R, R R R R and R is generally no more than 18 and preferably less than 6. The preferred halogens are fluorine and chlorine.

The invention also comprises an etfective anti-inflammatory amount of a compound of the invention in a nontoxic pharmaceutical carrier.

The reaction to obtain the compounds of the invention is represented as follows:

when the R and R (or the R and R groups) are different] wherein R, R R R and X are as defined above.

By reduction the double bond in Formula I or II is converted to a single bond. By halogenation, fluorine, chlorine, bromine, or iodine is introduced on the carbons to which R and R groups are attached. The nuclear sulfur can be oxidized to the sulfoxide and the sulfone by appropriate oxidizing agents.

Compounds of the structure I will be obtained when the sulfur atom of the ketene reactant attaches to the number 1 carbon of an unsymmetrical diene andcompounds of the structure II will be formed when the sulfur atom attaches to the number 4 carbon of an unsymmetrical diene. The formation of the two types of bridged compounds I and II illustrates the fact that if the cyclic diene is unsymmetrical, two isomeric products are possible and will generally be formed.

The Diels-Alder reaction may be carried out in the presence or absence of a solvent, the choice depending on the reactivity and physical state of the cyclic, conjugated diene. Very reactive dienes are conveniently diluted to control the reaction and facilitate heat removal. In the case of solid dienes it is usually appropriate to dissolve the diene in any inert solvent. Suitable solvents include dichloromethane, chloroform, carbon tetrachloride, 1,2-difluorotetrafiuoroethane, pentane, hexane, heptane, octane, benzene chlorobenzene, and carbon disulfide. The

- reaction is conveniently carried out at 0100 C., the low er temperatures being suitable for reactive dienes such as cyclopentadiene whereas with less reactive dienes an elevated temperature maybe required. For reactions run above the boiling point (52 C.) of the thiketene,.a closed reaction vessel is used. Purification of the products may Example 3.Cyclooctatetraene adduct R=R =R =R =H; n=0 a=double bond;

be carried out by conventional procedures, such as r'e- 5 X= CH CH crystallization, distillation, and the various types of chro- H matography.

SPECIFIC EMBODIMENTS OF THE INVENTION The following examples are non-limitative examples S in which all parts are as stated.

Eltample 1.-Cyclopentadiene adduct 0 2 R= 1= 2=R5;H; n=0; a=double bond; X= CH Cyclooctatetraene.(3.l2 g., 0.03 mol) and 5.82 g.

' (0.03 mol) of the thioketene were sealed in a glass tube and heated at 100 for 16 hr. Recrystallization of the producffrom methanol gave 7.0 g. (78% of 4-[2,2,2 O0 trifiuoro-l-(trifluoromethyl)ethylidene] 3 thiatricyclo s V [4.2.2.0 ]deca-7,9-diene in 3 crops, M.P. 49-50"; IR L 3067 cm.- '('=CH), 1575 (exocyclic C=C); H NMR 3)2 (CCl 2.85, 3.20 ppm. (triplets, 6-membered* ring r I bridgehead protons), 3.9, 4.4 (broad multiplets, satu- To 2.64 g. (0.04 mol) of freshly prepared cyclopenta- 25 ralfid y qp l, p Peak, cyclobutne diene dissolved in 10 ml. of dichloromethane was slowly superimposed on this a broader zfbsorPtwn added with stirring 7.76 g. (0.04 mol) of bis(trifiuoro correspondmg to, another (c q t0 methyDthioketene in 10 ml. of dichloromethane. The 19F NMR 1) P-P- (q temperature was kept at C. or less by cooling in ice. P Distillation gave 9.3 g. (89% yield) of 3-[2,2,2-trifiu0- Analyslsvcalcdfor 12 a s (D ro-l-(trifiuoromethyl)ethylidene] -'2 th'iabicyclo[2.2.l} 3, Found (p o i 4816; hept-S-ene, B.P. 69 7 mm.), 11 1.4486; IR 3977 10-62. v fi 1616 (exocychc 1575 (ring Example 4.Spiro[2,4]hepta-4,6-diene adduct C=C); F NMR (neat) -7.65, -l1.6 ppm. (quad- 1 2 5 l ruplets), using CCl FCCl F as standard. RZR R :R

Analysis.-Calcd. for 'c n F s (percent): 0, 41.55; e H, 2.32; S, 12.32. Found (percent): C, 41.45; H, 2.37; 7 5, 12.22. X: Example 2.-1,3-cyclohexadiene adduct 40 H,

R=R =R =R =H; 1 V a=double bond;

xr-crn S --C CF \S 5 Ten grams (0.0515 mol) of bis(trifiuoromethyl)thio- C(CF=): ke'tene in 8 ml. of dichloromethane was added to 6.77 I g. (0.0735 mol) of spir0[2,4]hepta-4,6-diene [K. Alder, H. J. Ache and F. H. Flock Chem..Ber. 93 1888 B1s(tr1fiuoromethyl)thioketene was added to an equimolar amount of 1,3-cycl'ohexadiene with cooling in ice 2 g of dlchmmmfihane coolmg and the mixture was allowed to stand for 16 hr. Fracation O the prpduct gave (91%). of tioriation yielded 3-[2,2,2-trifluoro-l-(trifiuoromethyl) 1 mfluorod (mfiwmmelhyl)ethylldenelSW0 ethylidene]-2-thiabicyclo[2.2.2]oct 5 ene, B.P. 79430" 1 5 'cyckpmpane' .(Lmmml), "D 1. 9 IR 1570 (C:C); 1H 45 (0.05 mm.), 1.4591. H NMR (neat) 0.53 NMR 1.6-2.4 p.p.m. (m, 4H), 4.00, 4.43 (broad doublets, (m, CYdOPmPYU' bndgeheads), 1H each), 632,680 (triplets, CH=CH); F NMR 652 (m, J 1O4,; (quadrup1ets) I Analyszs.Ca1cd. for C I-I F S (percent): C, 46.15; Analysis calcd for CmHsFBS (percent): C 4330; H, 2.82; S, 11.20 Found (percent): Q4629; H, 2.81; H, 2.94; s, 11.69. Found (percent): (3, 43.65; H, 2.95; 1109' S, 11.84. Example 5.1,1,5trimethylcyclopentadiene adduct fi z ii 611. CH CH R and 1 0-11 H W3 11:0 I 0 S \f V azdouble bond Dgtglliga =CWF32 CH3 =c 3,2

CH: CH1 X=/c /-C cm 7 cn.

Example 6.-Methylcyclopentadiene adduct One of R, R R R R or R is CH, and the remainder are each H;

n=; a= double bond; X= CR R Commercial methylcyclopentadiene dimer was cracked to give an isomeric mixture of methylcyclopentadienes:

To 12 g. (0.15 mol) of the methylcyclopentadienes in 25 ml. of dichloromethane was added 29.1 g. (0.15 mol) of bis(trifluoromethyl)thioketene in 15 m1. of dichloromethane at 15-20. Distillation gave 34.8 g. (83%) of an isomeric mixture of methyl-3-[2,2,2-trifluoro-1-(trifluoromethyDethylidene] 2 thiabicyclo[2.2.1]hept-5- enes, 6067 (5 mm.), 11 1.4419-1.4480, in which the methyl group is in one of the 1, 4, 5, 6 or 7 positions.

Analysis.Calcd. for C H F S (percent): C, 43.79; H, 2.94; S, 11.66. Found (percent): C, 43.60; H, 2.78; S, 11.30.

Example 7.Sulfone of cyclopentadiene adduct R=R =R =R =H; n=2; a=double bond; X= CH Procedure A.The compound of Example 1 (26 g., 0.1 mol) was dissolved in 50 ml. of dichloromethane and 43 g. (0.21 mol) of 85% m-chloroperbenzoic acid dissolved in 450 ml. CH Cl was added with cooling in ice. The solution was allowed to stand for 2 days at 4 and then washed with 5% aqueous sodium hydroxide and dried (Na SO The residue left after evaporation of the solvent was recrystallized from carbon tetrachloride to give 22.9 g. (78%) of 3-[2,2,2-trifluoro-1- (trifluoromethyl)ethylidene]-2 thiabicyclo[2.2.1]hept- S-ene 2,2-dioxide, M.P. 8286.

Procedure B.A mixture of 3 g. (0.0115 mol) of the compound of Example 1, ml. of acetic acid, and 3.5 ml. (0.034 mol) of 30% hydrogen peroxide was heated on a steam bath for 2 hr. Excess hydrogen peroxide was destroyed with 5% ruthenium on carbon and solvent was evaporated from the filtered solution. The residue was recrystallized from cyclohexane to give 0.98 g. (29%) of the sulfone, M.P. 82.7-84; H NMR (CCl 2.55 (t, bridge CH 3.94, 4.10 (bridgehead protons), 6.35 p.p.m. (t, CH=CH).

6 Analysis.-Calcd. for C H F O S (percent): C, 37.01; H, 2.07; S, 10.97. Found (percent): C, 37.00; H, 2.53; S, 10.93.

Example 8.Sulfoxide of cyclopentadiene adduct R=R =R =R =H; n=1; a=double bond; X= CH jiO CF 5 Z To the compound of Example 1 (26 g., 0.1 mol) dissolved in 50 ml. of dichloromethane was added at 1520 20.4 g. (0.1 mol) of m-chloroperbenzoic acid dissolved in 225 ml. of dichloromethane. The solution was then washed with 5% sodium bicarbonate solution and dried (Na SO The solvent was boiled 01f, finally under vacuum. The product was recrystallized from methanol by cooling in Dry Ice to give 10.26 g. (38%) of 3-[2,2,2- trifiuoro-l-(trifluoromethyl)ethylidene] 2 thiabicyclo- [2.2.1]hept-5-ene 2-oxide, M.P. 46-49"; H NMR (neat) 2.50 (center of quartet, bridge CH 4.12, 4.27 (singlets, bridgeheads), 6.01 (m, CH=CH).

Analysis.Calcd. for C H F OS (percent): C, 39.14;

H, 2.19; S, 11.61. Found (percent): C, 39.31; H, 1.96; S, 11.58.

Example 9.Dichloride of cyclopentadiene adduct R=R =H; R =R ==Cl;

igiirgle bond; X= CH W 01 s c1 c(c1=' To 5.2 g. (0.02 mol) of the compound of Example 1 in 10 ml. of dichloromethane was added 4 g. (0.03 mol) of sulfuryl chloride in portions. Sulfur dioxide was evolved. After 30 min. the product was distilled to give 5.85 g. (88%) of isomers of 5,6-dichloro-3-[2,2,2-trifluoro 1 (trifluoromethyl)ethylidene] 2 thiabicyclo- [2.2.1]heptane, B.P. 62 (0.2 mm.), n 1.48241.4835. NMR shows that no CH=CH is present in the product.

Analysis.Calcd. for C H Cl F S (percent): C, 32.65; H, 1.83; Cl, 21.42; S, 9.68. Found (percent): C, 32.83; H, 1.85; Cl, 20.48; S, 9.60.

The product can also be made by using chlorine in place of sulfuryl chloride.

Example 10.Dibromide of cyclopentadiene adduct To 15.6 g. (0.06 mol) of the compound of Example 1 in 15 ml. of dichloromethane was added 9.6 g. (0.06 mol) of bromine in 10 ml. of dichloromethane with cooling in ice. Evaporation of the solvent left 25.2 g. (100%) of 5 (or 6), 7-dibromo-3-[2,2,2-trifiuoro-l-(trilluoromethyDethylidene]-2-thiabicyclo[2.2.1]heptane. After recrystallization from hexane it melted at 4951. NMR of the product, together with that of Example 11 indicates that bromine addition is accompanied by rearrangement to form a dibrornide of the above structures.

Analysis.-Calcd. for C H Br F s (percent): C, 25.74; H, 1.44; Br, 38.06. Found (percent): C, 25.94; H, 1.69; Br, 38.05.

When chlorine is used in place of bromine, some 7- chloro product is also obtained.

Example l1.Bromo derivative of cyclopentadiene To g. (0.089 mol) of potassium t-butoxide suspended in 150 ml. of ether was added in portions 35 g. of the dibromide of Example 10 in 35 ml. of ether with stirring and cooling in ice. The mixture was stirred for 2 hr. at 24 and then filtered and distilled. The cut distilling at 43-50 (0.1 mm.) was recrystallized from hexane to give- 14.1 g. (50%) of 7-bromo-3-[2,2,2-trifiuoro-l-(trifluoromethyl)ethylidene]-2 thiabicyclohept- -5-ene, M.P. 62-63". NMR shows the presence of a CH=CH group.

Analysis.-Calcd. for C H BrF S (percent): C, 31.88; H, 1.49; Br, 23.57. Found (percent): C, 31.98; H, 1.55; Br, 23.28.

Example l2.Dihydro derivative of cyclopentadiene adduct R=R =R =R =H; n==0; a=single bond; X= CH A solution of 30 g. of the compound of Example 1 in 125 ml. of ethanol containing 1.7 g. of 5% palladium on carbon and 0.3 g. of palladium black was subjected to hydrogenation at room temperature and 40 psi. hydrogen pressure. After one hour the pressure drop had leveled 0E and the solution was filtered and distilled to give 25.4 g. (85%) of 3-[2,2,2-trifluoro-l-(trifiuoromethyl)ethylidene] -2-thiabicycl0[2.2.1]heptane, B.P. 70 (5 mm.), 2 1.4442. NMR shows that the.CH=CH- group of the starting material was reduced.

Analysis.-Calcd. for C H F S (percent): C, 41.23; H, 3.07; S, 12.23. Found (percent): C, 41.61; H, 3.10; S, 12.39.

A solution of 25.6 g. of the compound of Example 3 in ml. of alcohol containing 0.1 et platinum oxide was hydrogenated at room temperature and 40 psi. for 1 hr. The solution wasfiltered and distilled in a simple still at 5 mm. The white crystals (25.2 g.) were recrystallized from methanol to give 23.4 g. (91%) of 4-[2,2,2-trifluoro- 1-(trifiuoromethyl)ethylidene]-3 thiatricyc1o[4.2.2.0? deca-9-ene in 4 crops, M.P. 46-465". NMR indicates that the cyclobutene ring only was hydrogenated under these conditions.

Analysis-Calcd. for C H F S (percent): C, 48.00; H, 3.36; S, 10.68. Found (percent): C, 48.22; H, 3.16; S, 10.88. f i

More vigorous conditions are required to reduce the remaining cyclic double bond, for example, temperature of about 100 C. and a pressure of 500.p.'s.i.

Example 14. Pentamethyl-5-vinylcyclopentadiene alduct' R=R =R =R =CH n=0; a=double bond;

To 10.7 g. (0.066 mol) of pentamethyl-S-vinyl-cy'clm pentadiene [W. Shafer andH. Hellman, Angew. Chem., Int. Ed. Engl., 6, 618 (1967)] was added 12.8 g. (0.066 mol) of bis(trifluoromethyl)thioketene with'occasional cooling. Distillation gave 19.1 g. (81%) of two stereoisomers of 1,4,5,6,7-pentamethy1- 7 -vinyl-3 E2,2,2-trifiuoro 1 (trifluoromethyl)ethylidene] 2 -thiabicyclo[2.2.l] hept-S-ene, B.P. 74 (0.5 mm), r1 1.4799. Two, isomers arise because the vinyl group can be directed towa jd o'r away from the sulfur atom. By adding methanolto the mixture, cooling in Dry Ice, and filtering, 8.5 g. of a solid isomer, M.P. 50-52,was separated. i Y f Analysis.-Ca.lcd. for C H F S (percent): C, 53.93; H, 5.09; S, 9.00. Found (percent): C,' 53.77; H, 5.08; S, 9.12. i

The liquid isomer is obtained by distilling the filtrate from the crystallization Example 15.Spir[4.4]nona-l,3-diene adduct C(CF To 6.0 g. (0.05 mol) of spiro[4.4]nona-1,3-diene [E. O. Fischer and A. Werner, Chem. Ber., 93, 2075 (1960)] in 15 ml. of dichloromethane was added 9.70 g. (0.05 mol) of bis(trifluoromethyl)thioketene in ml. of dichloromethane with cooling in ice. Distillation gave 10.2 g. (72%) of 3 [2,2,2 trifluoro-1-(trifluoromethyl)ethylidene1spiro 2 thiabicyclo[2.2.1]hept-5-ene-7,l -cyclopentane, B.P. 65 (0.2 mm.), u 1.4685. H NMR (neat) 1.47 (S, 8H, cyclopentane ring), 3.83 and 4.01 (M, 2H, bridgeheads), 6.02 and 6.50 (M, CH-=CH).

Analysis.--Calcd. for C H F S (percent): C, 49.68; H, 3.85; S, 10.20. Found (percent): C, 49.92; H, 3.68; S, 10.26.

By way of further illustration are the compounds of Column B which can be made by the reaction of bis(trifluoromethyDthioketene with the compounds of Column A. In the case of unsymmetrical dienes in Column A, two isomers are produced as products, the ratio varying with the compound used. The mixture of isomers can be used as such, or if desired, separation can be effected by gas chromatography, or in favorable cases, by fractional distillation or crystallization.

Column A Column B 1 e s 1' I s ee cyelopentadienemmnnnzr; H2, 2, 2-trifluoro1-(t11fluoro methyD-ethylldenel-Z-thiablcyelo[2.2.1]hept-5-ene.

l-methyL..- 1- and i-methyl.

5-methyl.. 7 math 1, 2dlmethy 6- and 4, 5-dlmethyl 5, 5-dlmethyL- 7, 7-dlmethyl.

IL 2, S-tflmethyl l, 5, 6- and 4, 5, Mtrlmethyl.

1, 2, 3, 4-tetramethyl..--. 1, 4, 5, B-tetramethyl.

1, 2, 4, 5, B-pentamethyL- 1, 4, 6, 7, 7-pentamethyL 1, 2, 3, 4, 5, 5-hexameth l 1, 4, 5, 6, 7, Lhexamethyl.

1, 2, 4-trlethyl 1, 4, 5- and 1, 4, 5trlethyl.

l-ethyl-Z-methyll-ethylll-ti-methyl and 4-ethyl-5- 3, B-dflsopropyl-Lmathyh- 5, 7-dllsopropyl-1-methyl and 6, 7-dilso ropyH-methyl.

5-sec.-butyl- 7-sec.- utyl.

5-cyclopenty 'l-cyclo utyl;

1, 3-dlcyclohexyl- 1, 5- and 4, 6-dlcyc1ohexyl.

1, 4-trieyclohexyL 1, 4, 5- and 1, 4, o-trlcyclohexyl.

o 5- and hloro. 5, 5-trhnethylene (cyclic) 7, 7-trlmethylene; 5, B-tetramethylene 7-tetramethylene.

5, lz-(iilwethylpeutamethylene) 7, 7-(3, 3-diethylpentamethylene);

cy c

Column A Column B 5, 5-(1, Z-cyelohexylene) (cycllc). 7, 7-0, toyelohexylene).

. ill

5, 5-0, 1, 2, 2-tetramethy1) ethylene... 7, 7-(1, 1, 2, Z-tctrnmethyDethylene.

5,5-(butylethylene) 7, 7-(butylethylene) 5, 5-ethylene-1-methyl- 7, 7-ethylene-1-(and 4)methyl. 5, methoxy 7, 7-dlmethoxy. 5,5dlethoxy 7, 7-dlethoxy. 5, 5-trimethy1enediox 7, 7-trlmethylenedloxy. 5, 5-dihexyl0xy 7, 7-dlhexyloxy.

4 B a MOP l, 3-cyolohexadlene (H2, 2, Z-tdfluoro-l-(trlfluorw methyD-eth lidenel-2-th1ablcyclo[2.2.2 oct-5-ene. l-methyl 1- and 4-methyl. 1, E-dimeth 1, 8- and 4, 7-dlmeth yl. 1, 3, 5, 5-tetramethy1- 1, 5, 8, 8- and 4, 6, 7, 7-tetramethyl.

amoth uct of Example 3.

Halogenated compounds can be produced by starting with a halogenated diene or by adding halogen to a double bond in the product (Examples 10 and 11) to form a group. If hydrogen is present onone of the carbon atoms,

. the compound may be treated with a base such as potassium t-butoxide, potassium hydroxide, or sodium ethoxide, toeliminate HX and form the group Halogen may be again added to this group to form If a hydrogen atom is present on the carbon adjacent to the CX group, HX may be eliminated again to form Fluorine is conveniently introduced by adding [F to form 11 12 Elimination of H1 from this with alkali gives the group injectedv rats. Inhibition of paw volume increase in drug a F treated rats is indicative of anti-arthritic activity. l The compoundswere tested at 3'or more-dose levels. Dose-response curves were constructed for 2% inhibition of the treated group mean paw volume increases as compared to control group mean paw volume increase. The

IF-99 .+'FQSL star r a a ,I K JZ For example: i

-The oxidation of a typical product (Example 1) to the dose (mg/kg) reduired to-produce 60% 'inliibition of the sulfoxide and 'sulfone (Examples 7 and 8) has been illusmean paw volume increase (ED60) was determined from ,trated withthe use of hydrogen peroxide andm-chlorothe dose-response curve.

perbenzoic acid,. but other oxidizing agents such as per- The following table shows'the activity of compounds acetic acid, perbenzoic acid, perphthalic acid, permaleic of various preceding examples and of several anti acid, dichromates, .permanganates, and metaperiodates ca arthritic compounds currently in use.- be used for one, or more of these steps.

The hydrogenation of two compounds has been illus- TABLE j trated with palladiumand platinum as catalysts but other r M Mg./kg. to give catalysts, such as ruthenium, rhodium, Raney nickel, and Compound of example: 60% inhibition copper chromite may be used, as well as chemical reduc- 1 nu l 6 tion, e.g., with a diimide. 2 v 12 The anti-arthritic properties of these compounds are de- 3' ee .;a 9 termined by a test that is based on inhibition of the de- 4 Y a 4 velopment of arthritic processes induced in warm-blooded 5 i 65 animals, e.g. rats, by the subcutaneous injection of adf 6 i 24 juvant (mycobacterial cells suspended in mineral oil). Ad- 7 56 juvant-induced arthritis in rats was first described by Pear- 8 i v l 30 "son, C.Proc. Soc.Exp. BioLand Med.,9l,95 (1956). 10 v 1- V- 32 The established anti-arthritic. drugs are active in this. 7 1 12 V p a 16 test. The method employed follows: I3 7 y '1, 25

-Male, CFE rats weighing 150-200 grams and housed in p n 70 pairs in conventional suspended stainlesssteel cages were Cyclophosphamide '1 1 used in groups of 12-14 per drug dose level. The animals Alallllopflne i 5 received food in the form of Wayne LabBlocks and water Hydmcol'llsone v '7 1 I ad libitum during the entire experiment. The rats were lndomelllacill I 3 injected subcutaneously with 0.1 ml. of a suspension of Phcnylbutazone 5 Mycobacterium butyrz'cum (Difco heat-killed, lyophilized cells) in mineral'oil (5 mg./ml.) into the plantar area of The compound of Example 1 has also been foundvto the right hind paw. Mineral oil injected rats served as nonppr s Ce lular t n mane" response in animals "without arthritic C ntrols. affecting humoral immune responses. a 1 Drug treatment was "begun immediately after'flthe ad- It will be 9l.l the compounds of this j i j i d was continued f 14 days; Drugs vention can be administered to combat inflammation by were intubated once daily in 1 ml. per 100 grams of body y means h l y. delivers an eifective amount weight of PVA-Acacia medium (polyvinyl alcohol 1%, of the compound to the site of the inflammation, In some" gumacacia 5% and methylparaben 0.5%). Twenty-four applications this means, hat re nt l I of hours after the last dose the volume of the left hind paw ministration will b 5 FOI; p an effective (uninjected) was measured by mercury displacement amount of Compound of thisinventipn c n e li t t plethysmography. The animals were then lightly anestheir t y in h fi f da' n other instances. s -I tized with sodium pentobarbital and a 2 ml. blood sample cutaneous r intramuscular -ap m y be preferredwas obtained by cardiac puncture. The total white blood Alternatively concurrently, the compoundsof this'incell count (Coulter Counter, Coulter Electronics, Inc., vention can also' bev administered "orally or applied Hialeah, Fla.), the erythrocyte sedimentation rate (Wintopically. However, in most instances, oral administration trobe microhematocrit tube method) and the differential is the preferred route. v leucocyte count were determined. It will be understood that the dosage administeredwill The paw volume measurement is recorded as the meter be dependent on the age, health and weight of the reading from a transducer-indicator that expresses pror p the i y of h arthritic t er condition portionately the effect of mercury displacement on a being fl'ealfid; the kind f concurrent treatment and thesuitably oriented strain gauge. The system is calibrated nature of the efifect desired. Generally, a daily dosage of.

with a metal rod of known volume. The conversion of the active ingredient mpo nd will be from about-0.05110 50 mean meter reading to ml. is obtained from a standard milligrams per kilogram of body weight per day, t g curve. lower or higher amounts can be used. A preferred range- Increase in the paw volume of the uninjected hind paw is from about 0.1 to about 10 milligrams per kilogram is proportional to the development ofarthritis in adjuvant per day in one or more doses.

As previously discussed, the compounds of this invention can be administered by injection or taken orally and it therefore should be understood that they can be employed as useful compositions in dosage forms such as tablets, capsules, powder packets, liquid solutions, suspensions and elixirs for oral administration; liquid solutions for parenteral use, and in certain cases, suspensions for parenteral use. In such compositions, the active ingredient will ordinarily be present in an amount ranging from about 0.01% up to about 90% by weight based on the total weight of the composition.

Besides the active ingredient of this invention the composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, the solid carrier is a capsule which can be of the ordinary gelatin type. The capsule will comprise from about 0.1% to 75% by weight of a compound of this invention and about 99.9% to 25% of a carrier. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed. These capsules, tablets, and powders will generally constitute from about 0.5% to about 95% and preferably from 1% to 50% by weight of active ingredient. These dosage forms preferably contain from about to about 500 milligrams of active ingredient, with from about 25 milligrams to about 250 milligrams most preferred.

The pharmaceutical carrier can be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like. Sterile injectable solutions such as saline will ordinarily contain from about 0.5% to 25%, and preferably about 1% to 5% by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspension or elixir in which the active ingredient ordinarily will constitute from about 0.5 to and preferably about 1 to 10% by weight. The pharmaceutical carrier in such composition can be an aqueous vehicle such as a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in Remingtons Pharmaceutical Sciences by E. W. Martin, a well-known reference text in this field.

The following further examples illustrate specific pharmaceutical compositions for administration to a warmblooded animal.

Example 16 The compound of Example 3 is formulated conveniently in 10, 25, 50, 100 and 250 milligram amounts in standard two-piece hard gelatin capsules with a diluent such as starch, mannitol or lactose, for oral administration. In pharmacologic applications it is administered in these dosage forms at dosage levels in the range of 0.5 to 50 milligrams per kg. of body weight, as described above.

Example 17 The compound of Example 7 can be formulated for oral administration with suitable tableting adjuvants using a conventional tableting machine with the active ingredient constituting l to 50% by weight of the tablet. Other ingredients include gelatin, magnesium stearate, and starch or mannitol as described in the foregoing Martin reference.

Formulations of the type illustrated by Example 17 are also made with any of the active solid compounds of this invention.

Example 18 The compound of Example 1 can be formulated for oral administration in a soft gelatin capsule. Each capsule contains the following ingredients:

The active ingredient is dissolved in soybean oil at C., the solution is cooled and injected by means of a positive displacement pump into the gelatin (which contains the other ingredients) to form the capsule. The capsules are washed in petroleum ether and dried.

The concentration of active ingredient in oil can be varied to provide other dosage strengths. Other pharmaceutically acceptable oils can be used such as: peanut oil, cottonseed oil, corn oil and the like.

Example 19 The compound of Example 1 can be formulated for intramuscular injection by dissolving the compound in corn oil or sesame oil in concentrations of 0.1% to 1% (wt./vol.). In addition, 2 to 3% by volume of benzyl alcohol, N.F. may be included in the solution. The solution is clarified by filtration, placed in grass ampoules, sealed, and then sterilized by heating.

Example 20 A flavored elixir containing 50 mg. of the compound of Example 1 in every 5 ml. can be prepared by dissolving the compound in a fiavored solution of sorbitol containing up to 50% of ethyl alcohol U.S.P. so that the final concentration is 1% weight/volume.

The disclosure herein should not be taken as a recommendation to use the disclosed invention in any Way without full compliance with US. Food and Drug Laws and other laws and governmental regulations which may be applicable.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound having the formula wherein R and R alike or different, are H, alkyl or alkenyl of up to 4 carbon atoms, cycloalkyl of 5-6 carbon atoms, alkoxy of up to 6 carbon atoms, C1 or Br,

15 with the proviso that only one of R and R is Cl or Br; and when joined together, alkylene of 2-6 chain carbon atoms; or a trimethylenedioxy; and Y and Z each represent H or together represent a carboncarbon bond.

2. The compound of claim 1 which is 3-[2,2,2-trifluoro- 1-(trifiuoromethyl)ethylidene]-2 thiabicyclo[2.2.1]hept- S-ene.

3The compound of claim 1 which is 3-[2,2,2-trifiuoro- 1-(trifl'uoromethyl)ethylidene] 2 thiabicyclo[2.2.2]oct- $'-ene.

4'; The compound of claim 1 which is 4-[2,2,2-trifluoro- -1.-(trifluor0methyl) ethylidene] 3 thiatricyclo[4.2.2.0 deca-'7,9-diene.

t v Scribe-compound of claim 1 which is 3-[2,2,2-trifiuorol-(trifluoromethyl)cthylidene1spiro-2 thiabicyclo[2.2.l] bpt-S-ehe-T, l '-cyclopro pane.

-'--6; 'A con'ipound' of claim 1 which is methyl-3-[2,2,2- trifluoro 1 (trifiuoromethyl)ethylidene]-2-thiabicyclo [2.2.1]hept-5-ene.

'7. The compound of claim 1 which is 3-[2,2,2-trifiuorol-(trifluoromethyl)ethylidene]-2 thiabicyclo[2.2.l]hept- S-ene-Z-oxide.

8. The compound of claim 1 which is selected from the group consisting of 5,7- and 6,7-clibromo-3-[2,2,2- trifluoro l (trifluoromethyl)ethylidene] Z-thiabicyclo- [2.211heptane.

9. The compound of claim 1 which is 3-[2,2,2-trifluoro- 1-(trifiuoromethyl)ethylidene] 2 thiahicyclo [2.2.1]heptane.

10. The compound of claim 1 which is 4-[2,2,2-trifiu- I oro l (trifluoromethyl)ethylidene] 3 thiatricyclo- [4.2.2.0 dcca9-cne.

References Cited UNITED STATES PATENTS 3,406,184 10/1968 Raasch 26O-327 HENRY R. JILES, Primary Examiner C. M. S. IAISLE, Assistant Examiner US. Cl. X.R. 260-332.l, 332.3 P, 332.5; 424-275 mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 7j 8 1 Dated 3/73 Inventor(s) Maynard Stanley Raasch It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column Line Change .1

3 1A R "e." to --Y and 2-- i H II II I! Ii H A II H II Ll- 5 H I? II N H II I! II n 7 H II II 8 LL H H n 8 Y1 Ii 9 6 M" l I! 6 65 "a" to -Y and Z-- 6 65 "single bond", each occurrence, to -H-- 50 "a=single bond" to -Y and Z each=H-- l8 "4" to g g e, in

O a a 8 25 of to -of 7- 8 26 "3" to --8-- 15 12 21 M to is 7- i? ii 3 :21: 16 8 to --7-- l6 9 "3" to --8-- l6 2 cancel "the group consisting of 5, 7 and" Signed and sealed this 25th day of June 197M.

(SEAL) Attest:

EDWARD I I.FLETCHER,JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents 

